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MYSM1-AR Complex-Mediated Repression of Akt/C-Raf/GSK-3Β Signaling Impedes Castration-Resistant Prostate Cancer Growth

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MYSM1-AR Complex-Mediated Repression of Akt/C-Raf/GSK-3Β Signaling Impedes Castration-Resistant Prostate Cancer Growth www.aging-us.com AGING 2019, Vol. 11, No. 22 Research Paper MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3β signaling impedes castration-resistant prostate cancer growth Jinbo Sun1,*, Xiangnan Hu1,*, Yongheng Gao2,*, Qisheng Tang1, Zhining Zhao1,3, Wenjin Xi4, Fan Yang1, Wei Zhang1, Yue Song5, Bin Song1, Tao Wang4,6, He Wang1 1Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China 2Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China 3Clinical Laboratory, 451 Hospital of Chinese People's Liberation Army, Xi'an, Shaanxi 710054, China 4State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 5Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 6Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, Shaanxi 710032, China *Equal contribution Correspondence to: He Wang, Tao Wang, Bin Song; email: [email protected], [email protected], [email protected] Keywords: castration-resistant prostate cancer, growth, MYSM1, AR, Akt Received: August 20, 2019 Accepted: November 8, 2019 Published: November 24, 2019 Copyright: Sun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both in vitro and in vivo. Integrative database analyses and co-immunoprecipitation assays were performed to elucidate genomic association of MYSM1 and MYSM1-involved biological interaction network in PCa. We observed that MYSM1 were downregulated in CRPC compared to localized prostate tumors. Knockdown of MYSM1 promoted cell proliferation and suppressed senescence of CRPC cells under condition of androgen ablation. MYSM1 downregulation enhanced the tumorigenic ability in nude mice. Integrative bioinformatic analyses of the significantly associated genes with MYSM1 revealed MYSM1-correlated pathways, providing substantial clues as to the role of MYSM1 in PCa. MYSM1 was able to bind to androgen receptor instead of increasing its expression and knockdown of MYSM1 resulted in activation of Akt/c-Raf/GSK-3β signaling. Together, our findings indicate that MYSM1 is pivotal in CRPC pathogenesis and may be established as a potential target for future treatment. INTRODUCTION androgen synthesis or androgen receptor (AR) activity [2, 3], remain the mainstay treatment for locally advanced Prostate cancer (PCa) is one leading cause of cancer- or metastatic PCa. Unfortunately, the majority of patients related death among men in Western countries [1]. who have undergone ADT, even initially effective in Although surgical intervention has been shown to be tumor regression, eventually become resistant to the efficacious in eradicating localized PCa, androgen treatment [4] and progress to be castration-resistant PCa deprivation therapy (ADT), aimed at suppressing (CRPC). Castration resistance represents an enormous www.aging-us.com 10644 AGING clinical challenge and improvements in therapies as well In this study, we investigated the role of MYSM1 in as causative biomarkers for CRPC are in urgent need. carcinogenesis and progression of PCa. We revealed the decreased expression of MYSM1 and confirmed its AR with transcription activity is expressed in CRPC and tumor-suppressing functions in CRPC. Mechanistically, may play an important role in the setting of castration MYSM1 may exert its effect through interplay with AR via intratumoral androgen biosynthesis or interplay with and inhibiting the activation of PI3K/Akt signaling. This other growth-promoting and prosurvival pathways [5, 6]. work suggests that MYSM1 can be functionally essential The heterogeneity in AR expression or activity suggest for CRPC progression. that AR deficiency may be proposed as a potential way in which prostate cancer cells escape androgen RESULTS deprivation therapy [7], with compensatory signaling pathways activated concomitantly. The PI3K/Akt MYSM1 is downregulated in castration-resistant pathway is a well-established oncogenic pathway in prostate cancer and inversely correlated with human cancer [8–10] and is involved in resistance to progression of prostate cancer AR-targeted therapy in prostate cancer [11–13]. Alterations of nodes in PI3K/Akt pathway are reported To explore the expression of MYSM1 in human tumors, to occur in 42% of primary PCa and 70% of metastatic we performed web-based data mining to analyze tumors [14]. PTEN loss is frequently observed during The Cancer Genome Atlas (TCGA) datasets via PCa progression, especially in advanced prostate tumors GEPIA bioinformatics. We found that MYSM1 mRNA [15–17]. Thus, the PI3K/Akt pathway, which is levels were downregulated in ACC (adrenocortical antagonized by tumor suppressor PTEN, is constitutively carcinoma), CESC (cervical squamous cell carcinoma activated in prostate cancers with PTEN deficiency, and endocervical adenocarcinoma), COAD (colon leading to enhanced tumor cell survival, metastasis and adenocarcinoma), LUAD (lung adenocarcinoma), LUSC castration-resistant growth [12, 18, 19]. In addition, (lung squamous cell carcinoma), OV (ovarian serous reciprocal feedback regulation between PI3K/Akt and cystadenocarcinoma), READ (rectum adenocarcinoma), AR signaling has been identified as a potent mechanism SKCM (skin cutaneous melanoma), THCA (thyroid of CRPC progression and a crucial issue for carcinoma), UCEC (uterine corpus endometrial monotherapies targeting AR or PI3K/Akt pathways [20– carcinoma) and UCS (uterine carcinosarcoma) compared 22]. Combination therapy cotargeting PI3K/Akt and AR with normal tissues (Figure 1A, Supplementary Figure signaling leads to significant regression of prostate 1). In addition, MYSM1 expression was higher only in cancer when compared with monotherapies [23–25], DLBC (lymphoid neoplasm diffuse large B-cell suggesting a coordinative role in supporting tumor lymphoma) and THYM (thymoma) than that in normal survival. tissues (Figure 1A, Supplementary Figure 2). The expression of MYSM1 was decreased in PRAD (prostate Myb-like SWIRM and MPN domains 1 (MYSM1) acts adenocarcinoma) compared with that in normal prostate as a histone H2A deubiquitinase and is responsible for glands, but the change was not statistically significant removal of ubiquitin from monoubiquitinated histone (Figure 1A, 1B). Immunostaining analyses revealed that H2A at lysine 119 (H2AK119ub) [26]. Early studies MYSM1 protein levels were a little lower in prostate have linked MYSM1 to hematopoiesis where MYSM1 cancers when compared with benign prostatic modulates hematopoietic stem cell function and survival hyperplasia (Figure 1C). [27–29]. By coordinating histone modifications and transcription factors recruitment, MYSM1 plays a To further verify the expression of MYSM1 in prostate critical role in control of lymphocyte differentiation and cancer, we analyzed 2 microarray datasets (Grasso tissue development [29, 30]. Additionally, it has been Prostate and Taylor Prostate 3) from Oncomine reported that MYSM1 functions as a central negative database. Similarly, no significant differences of regulator of inflammatory response and immune system MYSM1 levels were observed between prostate cancers to prevent excessive inflammation and self-destructive and prostate glands (Figure 1D). However, we found immune response [31, 32]. Little is known about the role that compared with localized PCa patients, the of MYSM1 in human cancers. Few studies found that expression of MYSM1 was significantly downregulated MYSM1 was involved in melanoma growth and in metastatic castration-resistant prostate cancer colorectal cancer metastasis [33, 34]. It is worth noting (CRPC) patients (Figure 1E). Moreover, Oncomine that MYSM1 was reported to participate in regulation of analyses also revealed the clinically relevant signatures AR-dependent gene transcription in PTEN-deficient of MYSM1 expression in human PCa progression LNCaP cells [26]. However, the prostate-specific role of (Table 1). Although MYSM1 expression did not MYSM1, particularly its role in CRPC, has not been significantly correlate with age, PSA level, T stage, explored in detail. extracapsular extension, seminal vesicle involvement, www.aging-us.com 10645 AGING surgical margins status, hormone therapy, recurrence-free survival in PCa patients (Figure 1J, 1K). chemotherapy and radiotherapy (Table 1, P > 0.05), the The reason for insignificant correlation of MYSM1 level of MYSM1 was inversely associated with Gleason mRNA level with prognosis may be due in part to grade, Gleason score, N stage and recurrence status insufficient sample size. Taken together, these results (Figure 1F–1I). Kaplan-Meier analyses of Taylor suggest that dysregulation of MYSM1 may play a Prostate 3 cohort indicated no significant associations significant role in PCa progression and contribute to of MYSM1
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